The greatest risk factor for the development of degenerative disease is aging. As the median age in the world continues to rise along with it does the prevalence of degenerative diseases like Alzheimer's and Parkinson's. The hallmarks of the aged brain include stem cell attrition, loss of proteostasis, decreased mitochondrial function, and inflammation. These interconnected phenotypes create the environment in which degenerative diseases manifest and progress. The causes of these changes and the order in which they appear are still uncertain however their impact on cognitive function and disease progression is clear. Neuroinflammation describes an environment with an increased expression of pro-inflammatory cytokines; recently the cause of this inflammatory status has been attributed to a phenomenon known as priming. Microglia are the primary immune cell of the CNS and have diverse responsibilities such as a regulatory role in neurogenesis of the hippocampus. As microglia age they exhibit preference for the pro-inflammatory M1 polarization and a resistance to factors that induce an anti-inflammatory/tissue repair M2a/b phenotype this age dependent change is known as priming. Impaired microglial function has been shown to have deleterious effects on neurogenesis and long-term potentiation suggesting a role for priming in normal cognitive decline as well as the rapid progress of cognitive impairments that occur in degenerative diseases. My dissertation utilizes techniques such as mass spectrometry to study the age related changes that occur in cell types within the neurogenic niche. We recently performed a proteomic analysis of young and old microglia which revealed age-dependent alterations in metabolic pathways and actin/cytoskeletal organization. Analysis of upstream regulators predicted an inhibition of RICTOR and corticosterone. RICTOR is a central component in the mTORC2 complex one half of the mammalian target of rapamycin or mTOR signaling pathway, a pathway responsible for sensing nutrient abundance. Corticosterone is a mammalian glucocorticoid with powerful anti- inflammatory activity. We found that microglia where RICTOR had been inhibited with siRNA mimicked a primed phenotype and attenuated the response to glucocorticoids. These findings are supported by literature showing that mTORC2 inhibition produces an enhanced inflammatory response in macrophages to LPS. Therefore I hypothesize that age-dependent changes in mTORC2 activity contribute to the priming of microglia and that the mTORC2 signaling is an upstream regulator of glucocorticoid activity. The specific aims of this application: (i) to determine if and how mTORC2 activity is altered with age and how this alteration contributes to the priming of microglia (ii) to determine the role of glucocorticoid receptor activity in the manifestation of priming and the mechanism by which mTORC2 regulates this action (iii) to examine if microglial priming drives the reduction in neurogenesis and neural plasticity by selectively reducing RICTOR expression in the hippocampus of young mice.